Pneumocystis Pneumonia During Combined Therapy of Infliximab, Corticosteroid, and Azathioprine in a Patient with Crohn’s Disease
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- Itaba, S., Iwasa, T., Sadamoto, Y. et al. Dig Dis Sci (2007) 52: 1438. doi:10.1007/s10620-006-9575-5
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KeywordsCrohn’s diseaseInfliximabPneumocystis jiroveciPneumocystis pneumoniaCorticosteroid
Pneumocystis pneumonia (PCP) is one of the most frequent and severe opportunistic infections in immunocompromised patients. In recognition of its genetic and functional distinctiveness, the organism that causes human PCP has now been designated Pneumocystis jiroveci .
The number of patients who are receiving chronic immunosuppressive medication or have an altered immune system and are thus at risk of PCP is increasing rapidly . A recent report indicated that inflammatory disorders represent nearly 20% of the underlying diseases associated with PCP in HIV-negative patients . Furthermore, patients with Wegener’s granulomatosis and systemic lupus erythematosus show high risks of developing PCP among patients with inflammatory disorders . Although corticosteroids and other immunosuppressive drugs are frequently administered to patients with Crohn’s disease, there is only one report of a Crohn’s disease patient who developed PCP before infliximab was introduced for the treatment of Crohn’s disease .
Infliximab, a chimeric anti-tumor necrosis factor α (TNFα) monoclonal antibody, binds to TNFα with a high affinity, thereby neutralizing its biological activity . Infliximab induces remission in patients with moderately to severely active Crohn’s disease and can reduce the requirement for corticosteroid treatment . A recent study demonstrated that infliximab is also effective in patients with moderate to severe ulcerative colitis . The incidences of serious infections across infliximab-treated patients and placebo-treated groups were reported to be similar in the ACCENT 1 trial . Colombel et al. reported that infections were the most frequent cause of serious adverse events associated with the use of infliximab among their patients, and that 41 (8.2%) patients had infectious events considered to be at least possibily related to infliximab among 500 Crohn’s disease patients treated with infliximab . Serious infections, such as sepsis, miliary tuberculosis, disseminated coccidioidomycosis, histoplasmosis, listeriosis, and aspergillosis, have been observed in infliximab-treated patients and have led patient death in some instances . Following the introduction of infliximab administration for the treatment of Crohn’s disease, three cases of PCP related to infliximab were reported within a relatively short time period [11–13]. Here we report a case of PCP infection that followed combined therapy with infliximab, azathioprine, and corticosteroid and presented delayed recovery in a patient with Crohn’s disease.
A 57-year-old Japanese woman was admitted to our hospital with a 5-day history of fever, nonproductive cough, and shortness of breath. Her history of illness was appendicitis and gastric ulcer. She had a 21-year history of Crohn’s disease. She was maintained with enteral nutrition, mesalazine, oral corticosteroid (prednisolone, 25 mg), and azathioprine (50 mg). In September 2004, low-grade fever and general malaise continued, without any signs of infection. Thus, infusion of infliximab (5 mg/kg) for induction was initiated on 6 October 2004. A purified protein derivative skin test was negative and the patient’s chest radiography was normal before the infusion of infliximab. After two doses of infliximab (0 and 2 weeks) with total parenteral nutrition, her general condition improved and the fever was alleviated. Therefore, the scheduled infusion of infliximab was skipped at 6 weeks. However, her general condition worsened again, and a second induction therapy with infliximab was initiated on 27 December 2004. Two weeks after the second dose of infliximab (at 2 weeks), the administration of azathioprine was discontinued, since laboratory analyses revealed a decreased leukocyte count (1790 cells/μl) and lymphocyte count (340 cells/μl).
Data on pneumocystis pneumonia during administration of infliximab
Total doses of infliximab
Lymphocyte count (cells/μl)
Seddik et al. 
PSL (60 mg), AZA (150 mg)
Velayos & Sandborn 
AZA (75 mg)
Kaur & Mahl 
PSL (40 mg)
PSL (25 mg),
AZA (50 mg)
In the present case, we used corticosteroid, azathioprine, and infliximab for the treatment of active Crohn’s disease. Corticosteroids remain the mainstay of treatments for active Crohn’s disease but have many side effects. Corticosteroid use is thought to be the most common predisposition for developing PCP . As experienced in our case, glucocorticosteroid dependency, which is defined as a relapse of symptoms within 30 days of treatment or during dose tapering, that does not allow discontinuation of the drug is clinically important. The percentage of patients with corticosteroid dependency ranges from 20% to 36% . Therefore, we need to add other drugs with proven corticosteroid-sparing effects during corticosteroid treatment of corticosteroid-dependent Crohn’s disease patients.
Azathioprine is also widely used for the treatment of Crohn’s disease. A combination therapy with corticosteroid and azathioprine was reported to be superior to treatment with the corticosteroid alone in active Crohn’s disease . Furthermore, corticosteroid-sparing effects of azathioprine were demonstrated in active Crohn’s disease . The safety of azathioprine for the treatment of Crohn’s disease was confirmed in a study over a 30-year time period . There is only one reported case of inflammatory bowel disease that developed PCP during antimetabolite immunosuppressive therapy with 6-MP (50 mg/day) alone .
Corticosteroid-sparing effects have also been proved for infliximab . A three-dose induction regime of infliximab was more effective than a single dose . We found only three reported cases of PCP during the use of infliximab for treatment of Crohn’s disease in a review of the English literature [11–13]. The clinical data for these cases and the current case are reported in Table 1. The total doses of infliximab varied among the cases. Lymphocytopenia (<1000 cells/μl) was observed in all the cases, and the lymphocyte count was particularly low (175 cells/μl) in our case. One of the four cases died of PCP. Colombel et al. reported that the rate of infectious events was not correlated with the number of infusions of infliximab .
Prophylaxis criteria for PCP in patients without AIDS have not been well established in prospective controlled trials. Sepkowitz et al. suggested that immunosuppressed patients owing to an underlying disease or patients receiving other immunosuppressive therapy besides glucocorticoids at ≥ 20 mg/day for 4 weeks or more should receive prophylaxis . The occurrence of PCP in patients with autoimmune inflammatory disorders was clearly associated with major lymphopenia secondary to immunosuppressive therapy, which was present in almost all the patients . From these points of view, our patient should have received the prophylaxis for PCP.
Trimethoprim/sulfamethoxazole used at its full dose is a first-line treatment for PCP . This drug is routinely used for 21 days for treatment of PCP in HIV-infected patients. However, 14–17 days of treatment is recommended for non-HIV-associated PCP . TNF-α has important effects during PCP . The clearance of Pneumocystis jiroveci is delayed when TNF-α is neutralized by antibodies in animals with PCP . After a single infusion of infliximab, most patients receiving a 5 mg/kg dose still have a therapeutic concentration at 8 weeks but undetectable concentrations at 12 weeks . In the present case, drugs for PCP were not effective until 7 weeks after the last administration of infliximab. Therefore, delayed recovery from PCP may have been associated with infliximab when the concentration of infliximab was still considered to be in the therapeutic range.
Pareja et al. reported that adjunctive high-dose corticosteroids accelerate recovery in patients with severe non-HIV-associated PCP . However, whether or not adjunctive high-dose corticosteroids should be used for cases of PCP during administration of infliximab remains to be elucidated, since infliximab, an anti TNF-α antibody, itself suppresses the lung inflammation provoked by Pneumocystis jiroveci. Since the number of reported cases with PCP during the administration of infliximab is small, further investigations with a larger accumulation of cases are necessary.